ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1627G>A (p.Val543Met) (rs794727134)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724023 SCV000226184 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing
GeneDx RCV000724023 SCV000241509 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing The V543M variant has been previously reported in an individual with benign familial neonatal seizures; the variant was also identified in the affected father and 2 paternal aunts (Lee et al., 2017). Functional studies demonstrate the V543M variant causes a mild electrophysiological change in channel function compared to wild type (Lee et al., 2017). Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with with KCNQ2-related disorders (Stenson et al., 2014). The V543M variant is observed in 1/108796 (0.001%) alleles from individuals of European background (Lek et al., 2016). However, the V543M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics RCV000720278 SCV000851155 likely pathogenic Seizures 2017-03-01 criteria provided, single submitter clinical testing The p.V543M variant (also known as c.1627G>A), located in coding exon 14 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1627. The valine at codon 543 is replaced by methionine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of KCNQ2-related seizure disorder. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000765493 SCV000896789 uncertain significance Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001240137 SCV001413061 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 543 of the KCNQ2 protein (p.Val543Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of benign familial neonatal-infantile seizures or early infantile epileptic encephalopathy (PMID: 28399683, 31199083, 29056246, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 194446). This variant has been reported to affect KCNQ2 protein function (PMID: 28399683). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000781975 SCV000920430 likely pathogenic Benign familial neonatal seizures 1 2016-11-15 no assertion criteria provided clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001527628 SCV001738739 pathogenic Early infantile epileptic encephalopathy 7 2020-01-01 no assertion criteria provided clinical testing

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